The objective of this program is to continue and expand ongoing studies on the mechanism by which pyrimidine nucleoside analog active against HIV such as 3'azido-3'-deoxythymidine and congeners exert toxicity on bone marrow and other cells. The elicitation of these mechanisms may permit the development of a combination therapy with modulating agents that protect or reverse host toxicity without impairment of the anti-HIV activity of the drug under scrutiny. This project has two major aims: 1) the description of the biochemical and molecular mechanism responsible for the effects of AZT and its metabolite, 3'-amino-3'-deoxythymidine (AMT) in human marrow cells; and 2) the detailed characterization of the enzymatic reduction of AZT to AMT in human hepatocytes with the evaluation of potential drug-drug interactions through the cytochrome P- 450 pathway.